Kinase-independent signaling by PIM1 promotes drug resistance by increasing mitophagy and reducing oxidative stress.

PIM kinases are overexpressed in castration resistant prostate cancer (CRPC) and many small molecule PIM kinase inhibitors (smPIM inhibitors) have been designed to block the catalytic activity of PIM. However, smPIM inhibitors have shown limited efficacy in solid tumors. Notably, all these inhibitors share the common property that they increase total PIM protein levels, which limits their efficacy because PIM1 has kinase-independent pro-survival effects. Here, we identify high mobility box group 1 (HMGB1) as a novel PIM1 binding partner. Stabilization of PIM1 by smPIM inhibitors increases the cytosolic accumulation of HMGB1, which leads to activation of mitophagy and suppresses oxidative-stress induced cell death. Knockdown of PIM1/2/3 and/or HMGB1 sensitizes cancer cells to smPIM inhibitors. In contrast, treatment with a PIM PROTAC (PIMTAC) that we developed overcomes the kinase-independent pro-survival effects of PIM1 and is more effective than smPIM inhibitors in vitro and in vivo. These results uncover a mechanism of resistance that has limited the success of smPIM inhibitors and provides compelling evidence that targeted degradation of PIM is needed to realize its potential as an anti-cancer target.